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Diphenhydramine
| MedlinePlus = a682539 | pregnancy_AU = A | pregnancy_US = B | legal_status = Over-the-counter | routes_of_administration = Oral, parenteral (IM), parenteral (IV), topical, suppository | bioavailability = 40-60% | protein_bound = 98-99% | metabolism = Various cytochrome P450 liver enzymes: CYP2D6 (80%), 3A4 (10%) | elimination_half-life = 5.4 ± 1.8 hours (children) 9.2 ± 2.5 hours (adults) 13.5 ± 4.2 hours (elderly) | excretion = 94% through the urine, 6% through feces | CASNo_Ref = | CAS_number_Ref = | CAS_number = 58-73-1 | ATC_prefix = D04 | ATC_suffix = AA32 | ATC_supplemental = , | PubChem = 3100 | IUPHAR_ligand = 1224 | DrugBank_Ref = | DrugBank = DB01075 | ChemSpiderID_Ref = | ChemSpiderID = 2989 | UNII_Ref = | UNII = 8GTS82S83M | KEGG_Ref = | KEGG = D00669 | ChEBI_Ref = | ChEBI = 4636 | ChEMBL_Ref = | ChEMBL = 1620 | C = 17 | H = 21 | N = 1 | O = 1 | molecular_weight = 255.355 g/mol | smiles = O(CCN©C)C(c1ccccc1)c2ccccc2 | InChI = 1/C17H21NO/c1-18(2)13-14-19-17(15-9-5-3-6-10-15)16-11-7-4-8-12-16/h3-12,17H,13-14H2,1-2H3 | StdInChI_Ref = | StdInChI = 1S/C17H21NO/c1-18(2)13-14-19-17(15-9-5-3-6-10-15)16-11-7-4-8-12-16/h3-12,17H,13-14H2,1-2H3 | StdInChIKey_Ref = | StdInChIKey = ZZVUWRFHKOJYTH-UHFFFAOYSA-N }} '''Diphenhydramine hydrochloride' ( ; abbreviated DPH, sometimes DHM) is a first-generation antihistamine possessing anticholinergic, antitussive, antiemetic, and sedative properties which is mainly used to treat allergies. Like most other first-generation antihistamines, the drug also has a powerful hypnotic effect, and for this reason is often used as a non-prescription sleep aid. It is produced and marketed under the trade name Benadryl by McNeil-PPC (a division of Johnson & Johnson) in the U.S., Canada and South Africa (other trade names in other countries: Dimedrol, Daedalon). It is also available as a generic or store brand medication. It is also found in the name-brand products Nytol, Unisom, Tylenol PM, Excedrin PM, Midol PM and Advil PM, though some Unisom products contain doxylamine instead. It is available as an over-the-counter (OTC) or prescribed HCl injectable. It may also be used for the treatment of extrapyramidal side-effects of many antipsychotics, such as the tremors that haloperidol can cause. In addition, injectable diphenhydramine can be used for life-threatening reactions (anaphylaxis) to allergens such as bee stings, peanuts, or latex, rather than risking the side-effects of epinephrine. It is a member of the ethanolamine class of antihistaminergic agents. Diphenhydramine was one of the first known antihistamines, invented in 1943 by Dr. George Rieveschl, a former professor at the University of Cincinnati. In 1946, it became the first prescription antihistamine approved by the U.S. Food and Drug Administration (FDA). Usage / Yuseij / 用途 Medicinal / Medsinol / 藥用 Diphenhydramine is a first generation (typical) antihistamine used to treat a number of conditions including: allergic symptoms and itchiness, the common cold, insomnia, motion sickness, and extrapyramidal symptoms. Despite being one of the oldest antihistamines on the market, it is more effective than even some of the latest prescription drugs. Consequently, it is frequently used when an allergic reaction requires fast, effective reversal of the often dangerous effects of a massive histamine release. Diphenhydramine has sedative properties and is widely used in nonprescription sleep aids, with a maximum recommended dose of 50 mg (as the hydrochloride salt) being mandated by the U.S. FDA. In the United Kingdom, Australia, New Zealand, South Africa, and other countries, a 50–100 mg recommended dose is permitted. Diphenhydramine also has antiemetic properties which make it useful in treating the nausea that occurs in motion sickness. As it causes marked sedation in many individuals, the less sedating drug dimenhydrinate may be preferred for this purpose. The drug is an ingredient in several products sold as sleep aids, either alone or in combination with other ingredients such as acetaminophen (paracetamol). An example of the latter is Tylenol PM. Examples of products having diphenhydramine as the only active ingredient include Unisom gelcaps (the tablet form contains doxylamine, a different active ingredient), Tylenol Simply Sleep, Nytol, and Sominex (the version sold in the US; that sold in the UK uses promethazine). There are also topical formulations of diphenhydramine available, including creams, lotions, gels, and sprays. They are used to relieve itching, and have the advantage of causing much less systemic effect (i.e. drowsiness) than oral forms. As diphenhydramine is extensively metabolized by the liver, caution should be exercised when giving the drug to individuals with hepatic impairment. Abusive usage / Abyusiv yuseij / 濫用 Diphenhydramine is used both clinically and/or abusively in conjunction with opioids to relieve itching and act as an analgesia potentiator. It is used abusively as a hallucinogen, deliriant, depressant, or as a potentiator of alcohol and some opiates. Diphenhydramine is a moderate CYP2D6 inhibitor, and as a result can cause increases in blood levels of drugs that are CYP2D6 substrates. Diphenhydramine can also have an additive effect with other CNS depressants. Due to its interaction with a broad array of medications, combining diphenhydramine with other medications without medical supervision could have unanticipated and potentially hazardous results. Many users report a side effect profile consistent with atropine intoxication. This is due to antagonism of muscarinic acetylcholine receptors in both the central and autonomic nervous system which inhibits various signal transduction pathways. In the CNS, diphenhydramine readily crosses the blood-brain barrier, exerting effects within the visual and auditory cortex. Other CNS effects occur within the limbic system and hippocampus, causing confusion and temporary amnesia. Toxicology also manifests in the autonomic nervous system, causing urinary retention, pupil dilation, tachycardia, irregular urination, and dry skin and mucous membranes. Considerable overdosage can lead to myocardial infarction (heart attack), serious ventricular dysrhythmias, coma and death. Such a side-effect profile is thought to give ethanolamine-class antihistamines a relatively low abuse liability. The specific antidote for diphenhydramine poisoning is physostigmine, usually given by IV in hospital. Diphenhydramine is among the prohibited and controlled substances in the Republic of Zambia . Travelers are advised not to bring this drug into the country. Several Americans have been detained by the Zambian Drug Enforcement Commission for possession of Benadryl and other over-the-counter medications containing Diphenhydramine . Adverse effects Like many other first-generation antihistamines, diphenhydramine can cause strong sedation. As such, diphenhydramine has also been used as an anxiolytic because of this side-effect. It is also a potent anticholinergic agent, leading to the side-effects of dry mouth and throat, increased heart rate, pupil dilation, urinary retention, constipation, and, at high doses, hallucinations or delirium. Further side-effects include motor impairment (ataxia), flushed skin, blurred vision at nearpoint owing to lack of accommodation (cycloplegia), abnormal sensitivity to bright light (photophobia), difficulty concentrating, short-term memory loss, visual disturbances, irregular breathing, dizziness, irritability, itchy skin, confusion, decreased body temperature (in general, in the hands and/or feet), erectile dysfunction, excitability, and, although it can be used to treat nausea, higher doses may cause vomiting. Some side-effects, such as twitching, may be delayed until the drowsiness begins to cease and the person is in more of an awakening mode. Diphenhydramine also has local anesthetic properties, and has been used for patients allergic to common local anesthetics like lidocaine. There are several levels of evidence strongly indicating diphenhydramine (similar to chlorpheniramine) can block the delayed rectifier potassium channel and consequently prolong the QT-interval, leading to cardiac arrhythmias, such as torsade de pointes.(Nia et al. in Eur J Clin Pharmacol. 2010 Nov;66(11):1173-5. Epub 2010 Jul 31 Torsades de pointes tachycardia induced by common cold compound medication containing chlorpheniramine) Diphenhydramine is similar in its effects to dimenhydrinate, its 8-chlorotheophylline salt, although the latter is approximately 60% the potency in terms of required dosage and is slightly less sedating. Some patients have an allergic reaction to diphenhydramine in the form of hives. Since 2002, the US FDA requires special labeling warning against using multiple products that contain diphenhydramine. Diphenhydramine has been shown to build tolerance against its sedation effectiveness very quickly, with placebo-like results after a third day of common dosage. Paradoxical reactions to diphenhydramine are documented, in particular, among children, and it may cause excitation instead of sedation Diphenhydramine is on the "Beers list" to avoid in the elderly.NCQA’s HEDIS Measure: Use of High Risk Medications in the Elderly Chemistry Diphenhydramine, N'',''N-dimethyl-(diphenylmethoxy)ethylamine, is synthesized by a simple reaction of benzhydrylbromide and 2-dimethylaminoethanol:A. Grob, F. Hafliger, H. Martin, K. Getzi, (1946)G. Riveschl, (1947)G. Riveschl, (1947) Pharmacology Diphenhydramine is an inverse agonist of the histamine H1 receptor. By blocking histamine in the capillaries it can reduce the intensity of allergic symptoms. Diphenhydramine crosses the blood-brain barrier (BBB) and antagonizes the H1 receptors centrally. Its effects on central H1 receptors causes drowsiness. Like many other first-generation antihistamines, diphenhydramine is also a potent competitive antagonist of muscarinic cholinergic receptors, and, as such, at high doses can cause anticholinergic syndrome.http://emedicine.medscape.com/article/812828-overview. In the 1960s, diphenhydramine was found to inhibit reuptake of the neurotransmitter serotonin. This discovery led to a search for viable antidepressants with similar structures and fewer side-effects, culminating in the invention of fluoxetine (Prozac), a selective serotonin reuptake inhibitor (SSRI).Domino, Edward F. History of Modern Psychopharmacology: A Personal View With an Emphasis on Antidepressants. Psychosomatic Medicine 61:591-598 (1999).http://meeting.chestjournal.org/cgi/content/abstract/134/4/c4002 A similar search had previously led to the synthesis of the first SSRI, zimelidine, from brompheniramine, also an antihistamine. Diphenhydramine also acts as a sodium channel blocker, which is responsible for its actions as a local anesthetic. Quantification Diphenhydramine may be quantitated in blood, plasma, or serum to monitor therapy, confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest, or assist in a medicolegal death investigation. Blood or plasma diphenhydramine concentrations are usually in a range of 10-150 μg/L in persons taking the drug orally for its antiemetic, antihistaminic or sedative effects, 0.7-2.7 mg/L (700-2700 μg/L) in those arrested for impaired driving, 1–5 mg/L in survivors of acute overdosage and 5–30 mg/L in victims of fatal overdosage. In some jurisdictions, diphenhydramine is often present in postmortem specimens collected during investigation of sudden infant deaths; the drug may play a role in these events. R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 489-492. See also / Si osou / 參看 * Akathisia * Acrivastine * Anticholinergic * Cetirizine * Chlorpheniramine maleate * H1 antagonist References / Riförènses / 參考資料 Notes / Nouts / 備註 Sources / Sōrses / 資料來源 * * J.A. Lieberman, History of the use of antidepressants in primary care. Primary Care Companion, J. Clinical Psychiatry, 2003; 5 (supplement 7). *伊藤勝昭ほか編集　『新獣医薬理学 第二版』 近代出版　2004年　ISBN 4874021018 External links / Ikstörnol liŋks / 外部連結 * Prescription Information (PDF) * Diphenhydramine University of Maryland Medical Center Medical References * Diphenhydramine entry for recreational use at Drugs-Wiki * Man 'took own life' in courtroom - suicide by Diphenhydramine - BBC News Category:Medsin Category:Antihistamines Category:Antiemetics Category:Deliriants Category:H1 receptor antagonists Category:Muscarinic antagonists Category:Sedatives Category:Hypnotics Category:Tardive dyskinesia Category:Ethers Category:Amines Category:Serotonin reuptake inhibitors